Clear cell renal cell carcinoma (ccRCC) is unique from many other tumor types, as biomarkers of response to immunotherapy, such as tumor mutational burden, do not have predictive value for this disease. Au and colleagues postulated that the failure to identify biomarkers of response to checkpoint blockade immunotherapy was due to high levels of intratumoral heterogeneity found in ccRCC. Thus, they established a phase 2 clinical trial of treatment-naïve metastatic ccRCC patients in which the multiple intratumoral biopsies were sampled at various time periods in order to track disease progression. Patients were divided into two groups, responders and nonresponders, and samples from both were subjected to multiomic and immune microenvironment analyses. Consistent with previous analysis, no correlation was found between various genomic signatures and response to nivolumab (anti-PD1). Importantly, responders exhibited a higher number of expanded T-cell receptor (TCR) clones pretreatment than nonresponders, consistent with some pre-existing immunity. Maintenance of...

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